The overall objective of this proposal is to investigate whether the alterations in the opioidergic system modulate the development and progression of heart failure. Although infective endocarditis is well- documented to occur and its clinical features well described in opiate addicts, few studies have focused on the acute or chronic effects of opiates on heart diseases other than infective endocarditis. Likewise, the role of the opioidergic system in the deterioration of heart function remains entirely speculative. A broad multidisciplinary approach will be established that combines diverse techniques (integrative physiology, molecular biology, and pharmacology) and will integrate basic information at the cellular level with information at the whole organ/animal level. To ascertain the involvement of the opioidergic system in the progression of heart failure, we will assess mu-, delta-, and kappa-opioid receptor expression and functionality as well as alterations in endogenous opioid peptide precursors and their peptide products at various stages in the progression of heart failure via molecular and pharmacological methods. Furthermore, the cardiac effects (i.e, remodeling and function) during chronic opiate/opioid administration or opioid receptor antagonism will be evaluated by echocardiography and left ventricular catheterizations along with histological and morphological techniques. A unique hamster strain which is predisposed to hypertrophic cardiomyopathy and heart failure will be used to test the involvement of the opioidergic system in the development and progression to heart failure and how each opioid receptor type modulates the progression to heart failure following chronic opiate/opioid abuse. Results of this proposal will provide novel insights into the relationship between heart failure and the opioidergic system, as modulated by chronic opiate/opioid use. Opiate addiction and cardiovascular disease are prevalent as well as costly public health issues in the United States. Understanding the molecular and cellular basis of the opioidergic system in heart failure is a necessary step towards elucidating its role in cardiovascular disease. These findings may prove to be useful in identifying novel diagnostic or biomarkers for a predisposition to or early stages of heart failure, thus allowing earlier treatment and prevention in susceptible patients. Also, these findings may result in reassessment of medical care and treatment in patients exposed to chronic opiate/opioid administration.